Polyendocrine Metabolic Ovarian Syndrome Management

The goals of therapy for polycystic ovarian syndrome include reducing risk factors for type 2 DM and CVD, managing underlying metabolic abnormalities, addressing overweight and obesity, treating hyperandrogenic features, preventing endometrial hyperplasia and carcinoma, inducing ovulation in women who wish to become pregnant, and providing contraception for those who are not pursuing pregnancy. A specialist referral (eg endocrinologist, gynecologist, or dietitian) may be needed for the management of metabolic abnormalities, ovulatory dysfunction, and weight concerns.

Management for Amenorrhea

Medroxyprogesterone acetate

Medroxyprogesterone acetate is a synthetic cyclic progestogen that inhibits ovulation, resulting in endometrial thinning. This has some androgenic and anabolic activities but no estrogenic effects. This is used mainly for endometrial protection from unopposed estrogen-induced hyperplasia and cycle regulation in women who are not trying to conceive. Medroxyprogesterone acetate induces withdrawal bleeding in polycystic ovarian syndrome women who have irregular menstrual cycles to help re-establish predictable cycles and manages abnormal bleeding. This may be given for patients who cannot take estrogen-containing pills or those who do not wish to take oral contraceptives (OCs) for cycle control. Low cyclic dosing used in polycystic ovarian syndrome for endometrial protection and scheduled bleeding does not provide birth control.

Management for Excess Androgen¹

Combination Oral Contraceptives (COCs)²

Combination oral contraceptives are the first-line agents for managing menstrual irregularity and hyperandrogenism. These are used to establish regular menstrual cycles and have been shown to control hirsutism and acne in polycystic ovarian syndrome. Patients should be made aware that it may take a minimum of 6 months to notice a benefit in hirsutism and acne. These may be used in polycystic ovarian syndrome patients who do not desire pregnancy. Low-dose preparations with minimal androgenic potential (eg Norgestimate, Desogestrel, Gestodene, Drospirenone, Dienogest and Etynodiol diacetate; 20-30 mcg of Ethinyl estradiol or equivalent) are preferred for long-term management. Consider natural estrogen preparations balancing efficacy, side effects, metabolic risk profile, cost, and availability. Combination oral contraceptives help reduce the risk of endometrial hyperplasia and carcinoma by antagonizing estrogen’s proliferative effect on the endometrium through withdrawal bleeding.

Combination oral contraceptives inhibit gonadotropin stimulation of the ovary, resulting in reduced androgen production. These cause the lowering of LH levels without surges, and the estrogen component stimulates SHBG production by the liver, which lowers bioavailable androgen. This androgen suppression causes significant increases in circulating triglyceride and HDL cholesterol levels. Assess the patient for risk factors (eg high BMI, hypertension, hyperlipidemia) when prescribing combination oral contraceptives and also for risk factors for venous thromboembolism (VTE) (eg age, obesity, family history of VTE). Follow WHO COC general population guidelines for relative and absolute contraindications and risks.

¹Please see Acne Vulgaris disease management chart for further information. 
²Many combination oral contraceptives are available. Please see the latest MIMS for specific formulations and prescribing information.

Antiandrogen Agents

Example drugs: Cyproterone acetate, Finasteride, Flutamide, Spironolactone

For the treatment of hirsutism and androgen-related alopecia, antiandrogen agents may be considered in combination with combination oral contraceptives or as monotherapy in women who are intolerant of or have contraindications to combination oral contraceptives, provided effective contraception is ensured due to teratogenic risk (undervirilization of male fetus). For hirsutism, consider combination therapy with COCs if without symptom improvement after ≥6 months of COC use and cosmetic treatment. Discontinue antiandrogen therapy if contemplating pregnancy. All appear to offer some benefit, although the best choice for hirsutism in polycystic ovarian syndrome is unknown. Evidence of use in polycystic ovarian syndrome is relatively limited.

Cyproterone acetate is a synthetic progestin that blocks androgen binding in target tissues. This is used for managing hirsutism, androgenic alopecia, and acne. Doses ≥10 mg are not advised due to an increased risk for meningioma. Cyproterone acetate combined with estrogen provides control of menses and contraception. This has been used successfully to treat hirsutism and severe acne caused by androgen excess. Ethinyl estradiol 35 mcg plus Cyproterone acetate should not be considered first-line treatment due to adverse effects, including VTE risks.







Finasteride is a 5-alpha reductase inhibitor that acts by inhibiting the conversion of testosterone to dihydrotestosterone and by blocking androgen receptors. This is an antiandrogen that is as effective as Spironolactone in treating hirsutism but should only be considered in women who do not desire pregnancy. This is better tolerated than other antiandrogens with minimal hepatic and renal toxicity.

Flutamide is an acetanilid, non-steroidal, orally active antiandrogen that inhibits androgen uptake and inhibits nuclear binding of androgen in target tissues. This is used for managing hirsutism and has an increased risk of severe hepatotoxicity.

Spironolactone is a mineralocorticoid antagonist with a structure similar to testosterone and competes with androgen by binding to receptors. This is useful in the treatment of hirsutism and acne in women who do not desire pregnancy. This may reduce the caliber and growth rate of hair in 40-80% of cases but may require 8-14 months before clinical effects can be observed. Menses occasionally resumes. This is usually combined with combination oral contraceptives if hyperandrogenic symptoms are unresponsive to COC monotherapy and to prevent erratic vaginal bleeding.

Eflornithine

Eflornithine inhibits the growth of facial hair. The onset of action may take 4-8 weeks for facial hirsutism. The postulated mechanism of action includes irreversible inhibition of ornithine decarboxylase activity in the skin, resulting in a reduced rate of hair growth in hair follicles.

Gonadotropin-releasing Hormone (GnRH) Analogues

Gonadotropin-releasing hormone (GnRH) analogues have been used especially in severe ovarian hyperandrogenism. These suppress androgen production by the ovaries. Use is limited by cost and complications due to long-term estrogen deficiency and requires concurrent estrogen/progestin add-back therapy.

Management for Metabolic Risks (Insulin Resistance and Glucose Intolerance)

Metformin 







Metformin inhibits hepatic glucose output, increases sensitivity of peripheral tissues to insulin action, and enhances muscle glucose uptake, leading to a decrease in insulin levels. This reduces ovarian gluconeogenesis, decreasing ovarian androgen production. This has been shown to significantly improve insulin concentration, insulin sensitivity, and serum androgen concentration, along with a reduction in LH and an increase in SHBG concentration. This has been associated with a decrease in features of metabolic syndrome in premenopausal polycystic ovarian syndrome patients. In hyperinsulinemic polycystic ovarian syndrome, Metformin has been used to restore menstrual cyclicity and induce ovulation with and without the addition of Clomifene.

Metformin may be considered as a second-line agent in those who cannot take or are intolerant of hormonal contraceptives for the treatment of anovulation. Metformin and lifestyle modification should be considered in adolescents and in adults for weight treatment (BMI ≥25 kg/m²) and for hormonal and metabolic outcomes. Metformin should be considered over Inositol in patients with hirsutism and central obesity. Consider combination therapy with Metformin and combination oral contraceptive in patients whose treatment with lifestyle modification and combination oral contraceptive had been unsuccessful for management of metabolic features. This could be considered in adolescents with polycystic ovarian syndrome and BMI ≥25 kg/m² if both combination oral contraceptive and lifestyle changes failed to achieve treatment goals. Metformin and COC combination therapy is most beneficial in high metabolic risk groups (eg individuals with diabetes risk factors, impaired glucose tolerance, or high-risk ethnic groups). Metformin appears safe with long-term use but ongoing monitoring is required, and it has been associated with low levels of vitamin B12. Side effects, including gastrointestinal effects, are dose-related and self-limiting. Consider starting at a low dose with 500-mg increments every 1-2 weeks.

Other Agents

Inositol

Inositol acts as a secondary messenger and is involved in insulin signaling transduction. Myo-inositol is a stereo-isomer of Inositol which, upon insulin stimulation, is converted to D-chiro-inositol, which stimulates glycogen production and facilitates glucose uptake. This may be considered in women with polycystic ovarian syndrome. This is currently considered an experimental therapeutic agent in polycystic ovarian syndrome. Emerging evidence shows efficacy, though further research is needed.

Anti-obesity Agents

Example drugs: Glucagon-like peptide-1 (GLP-1) receptor agonists (eg Liraglutide, Semaglutide), Orlistat

Anti-obesity agents may be considered in addition to lifestyle modification for the management of higher weight in adult patients with polycystic ovarian syndrome.

Lifestyle Modification

Lifestyle modification is recommended in all polycystic ovarian syndrome patients. Diet modification with healthy eating, regular exercise, and weight loss in obese patients all contribute to reestablishing insulin sensitivity and optimizing general health and quality of life. Benefits should be emphasized during preconception counseling. In women with polycystic ovarian syndrome, excess body fat aggravates insulin resistance and its associated clinical consequences. Central obesity and high BMI have a major impact on the development of hyperinsulinemia and hyperandrogenism. Goal setting and self-monitoring, which are specific, measurable, achievable, realistic, and timely (SMART) can help achieve lifestyle goals. All patient interactions should be patient-centered and should consider individualized healthy lifestyle preferences, including cultural, socioeconomic, and ethnic differences. A respectful and considerate approach should be considered when assessing a patient's weight due to associated negative body image, low self-esteem, and/or related stigma. Polycystic ovarian syndrome patients with normal body habitus should be advised to continue this and to maintain their body weight within the normal range.

Polycystic ovarian syndrome patients should be informed of and screened for risk factors of CVD such as cigarette smoking, obesity, dyslipidemia, type 2 DM or impaired glucose tolerance, insulin resistance, family history of early CVD, subclinical vascular disease, hypertension, metabolic syndrome, OSA, MASH, and the absence of physical activity. 

Polycystic ovarian syndrome patients are more likely to develop mood disorders and should also be screened for anxiety and depressive symptoms using validated screening tools to ensure adherence to management and treatment. If positive, a specialist referral for further assessment and/or treatment may be done. Behavioral strategies, including goal-setting, self-monitoring, assertiveness training, problem-solving, slower eating, stimulus control, reinforcing changes, and relapse prevention, can help optimize a healthy lifestyle, weight management, and a patient's emotional well-being.

Diet Modification

There is no particular food plan that is recommended for polycystic ovarian syndrome. It is recommended to follow general healthy eating practices. Frequent feedings (4-6 times/day) may be helpful to avoid hypoglycemia and hunger. Hypoglycemia can lead to cravings and poor food choices. To promote weight loss, diet should be modified to an intake of carbohydrates with a low glycemic index and a reduced intake of fat and simple sugars. A high-protein diet appears as effective as a high-carbohydrate diet as long as fat and total calories are comparable. Consider reducing intake by 500-750 kcal/day, taking into consideration the patient’s weight, energy requirements, and activity level.

Exercise 







Weight reduction and exercise can help reverse the metabolic problems in polycystic ovarian syndrome by improving ovarian function and the associated hormonal aberrations. Vigorous activity at 75-150 minutes/week or moderate-intensity activity at 150-300 minutes/week, or a combination of both, together with muscle strengthening on two non-consecutive days/week, is encouraged to prevent weight gain and to maintain health. Activities of vigorous intensity at a minimum of 150 minutes/week or moderate intensity at a minimum of 250 minutes/week, or a combination of both, and strengthening of the major muscle groups on two non-consecutive days/week are encouraged to lose modest weight and to prevent regained weight. Aerobic exercise is best performed in 10-minute sessions with the aim of achieving ≥30 minutes of exercise per day on most days. Physical activity can be incidental or structured; self-monitoring, including the use of fitness tracking devices and technologies, could support and promote active lifestyles. Exercise decreases the risk of diabetes and CVD. Improvement in physical fitness and reduction in body fat will assist in resumption of ovulation and increase in fertility, especially in anovulatory obese women with polycystic ovarian syndrome.

Weight Reduction 







Weight reduction is associated with improved pregnancy rates and decreased hirsutism, as well as improvements in glucose and lipid levels. This helps lower circulating androgen levels, leading to spontaneous resumption of menses. This improves insulin resistance in obese patients. A 5-10% weight loss in 6 months is considered successful. It is estimated that a loss of 5-10% of body weight can restore reproductive function in 55-100% of polycystic ovarian syndrome patients within 6 months of a weight-reducing program. Hirsutism can also improve within 6-9 months of weight loss. Body mass index and waist circumference categories that are adolescent and ethnic-specific should be considered to optimize lifestyle and weight management. Anti-obesity medications or bariatric surgery can be considered with lifestyle intervention as per general population guidelines. Consider treatment availability, cost, side effects, contraindications and regulatory status, and avoid pregnancy while on therapy.

Management for Hirsutism

If hirsutism is moderate and localized, it may be treated with hair removal by shaving, plucking, waxing, bleaching, laser therapy, electrolysis, or depilatory creams. In more severe hair growth, alternative methods can be used until androgen-suppressing therapies take effect. Treatment is often palliative rather than curative.